Method for the 1,3 dipolar cycloaddition of organic compounds in a microreactor

ABSTRACT

The invention relates to a method for the 1,3 dipolar cycloaddition of organic compounds, characterized in that the reaction is carried out in a microreactor.

The present invention relates to a method for the 1,3-dipolarcycloaddition of organic compounds.

The 1,3-dipolar cycloaddition of organic compounds is a method which iscarried out very frequently in the chemical industry and whose greatimportance is also reflected in numerous publications on this subject.

However, the performance of 1,3-dipolar cycloadditions of organiccompounds on an industrial scale is associated with safety problems andrisks. Firstly, use is frequently made of relatively large amounts ofhighly toxic chemical substances, which even alone represent aconsiderable risk to humans and the environment, and secondly1,3-dipolar cycloadditions of organic compounds frequently proceed veryhighly exothermically, which means that there is an increased risk ofexplosion when these reactions are carried out on an industrial scale.The attainment of official approval in accordance with the GermanFederal Emissions Protection Act (BimschG) for the operation of plantsfor the 1,3-dipolar cycloaddition of organic compounds on an industrialscale is therefore associated with considerable effort.

The object of the present invention is therefore to provide a method forthe 1,3-dipolar cycloaddition of organic compounds which avoids theabove-mentioned disadvantages. The aim is, in particular, for it to bepossible for this method to be carried out in a simple, reproduciblemanner with increased safety for humans and the environment and withgood yields and for the reaction conditions to be readily controllable.

This object is achieved, surprisingly, by the method according to theinvention for the 1,3-dipolar cycloaddition of organic compounds, inwhich at least one organic compound in liquid or dissolved form is mixedwith at least one dipolarophile in liquid or dissolved form in at leastone microreactor and reacted for a residence time, and the organiccycloaddition compound formed is, if desired, isolated from the reactionmixture.

Advantageous embodiments of the method according to the invention aredescribed in the sub-claims.

In accordance with the invention, an organic compound or a mixture of atleast two of these compounds can be employed in the claimed method. In apreferred embodiment, in each case only one organic compound is used.

For the puropses of the invention, at least one organic compound having1,3-dipolar properties is reacted with at least one dipolarophile or theorganic compound simultaneously contains at least one functional grouphaving 1,3-dipolar properties and at least one functional group havingdipolarophilic properties. The 1,3-dipolar and dipolarophilic functionalgroups may in each case be identical or different. Preferably, in eachcase only one 1,3-dipolar group and one dipolarophilic group arepresent. As a consequence, both intermolecular and intramolecularcycloadditions are covered.

The organic compounds can be employed as pure compounds or prepared insitu from suitable precursor compounds and scavenged directly bydipolarophiles with formation of the corresponding cycloadditionproduct(s). The organic compounds are preferably prepared in situ andscavenged directly by dipolarophiles.

For the purposes of the invention, a microreactor is a reactor having avolume of ≦1000 μl in which the liquids and/or solutions are intimatelymixed at least once. The volume of the reactor is preferably ≦100 μl,particularly preferably ≦50 μl.

The microreactor is preferably made from thin silicon structuresconnected to one another.

The microreactor is preferably a miniaturised flow reactor, particularlypreferably a static micromixer. The microreactor is very particularlypreferably a static micromixer as described in the patent applicationwith the international publication number WO 96/30113, which isincorporated herein by way of reference and is regarded as part of thedisclosure.

A microreactor of this type has small channels in which liquids and/orchemical compounds in the form of solutions are mixed with one anotherby means of the kinetic energy of the flowing liquids and/or solutions.

The channels of the microreactor preferably have a diameter of from 10to 1000 μm, particularly preferably from 20 to 800 μm and veryparticularly preferably from 30 to 400 μm.

The liquids and/or solutions are preferably pumped into the microreactorin such a way that they flow through the latter at a flow rate of from0.01 μl/min to 100 ml/min, particularly preferably from 1 μl/min to 1ml/min.

In accordance with the invention, the microreactor is preferablyheatable.

In accordance with the invention, the microreactor is preferablyconnected via an outlet to at least one residence zone, preferably acapillary, particularly preferably a heatable capillary. After mixing inthe microreactor, the liquids and/or solutions are fed into thisresidence zone or capillary in order to extend their residence time.

For the purposes of the invention, the residence time is the timebetween mixing of the starting materials and work-up of the resultantreaction solution for analysis or isolation of the desired product(s).

The residence time necessary in the method according to the inventiondepends on various parameters, such as, for example, the temperature orreactivity of the starting materials. It is possible for the personskilled in the art to match the residence time to these variousparameters and thus to achieve an optimum course of the reaction.

The residence time of the reaction solution in the system used,comprising at least one microreactor and, if desired, a residence zonecan be set through the choice of the flow rate of the liquids and/orsolutions employed.

The reaction mixture is likewise preferably passed through two or moremicroreactors connected in series. This achieves an extension of theresidence time, even at an increased flow rate, and the 1,3-dipolarcycloaddition components employed are reacted to such an extent that anoptimum product yield of the desired cycloaddition product(s) isachieved.

In a further embodiment, the reaction mixture is passed through two ormore microreactors arranged in parallel in order to increase thethroughput.

In another preferred embodiment of the method according to theinvention, the number and arrangement of the channels in one or moremicroreactors are varied in such a way that the residence time isextended, likewise resulting in an optimum yield of the desiredcycloaddition product(s) at an increased flow rate.

The residence time of the reaction solution in the microreactor, whereappropriate in the microreactor and the residence zone, is preferably≦15 hours, particularly preferably ≦3 hours, very particularlypreferably ≦1 hour.

The method according to the invention can be carried out in a very broadtemperature range, which is essentially restricted by the heatresistance of the materials employed for the construction of themicroreactor, any residence zone and further constituents, such as, forexample, connections and seals, and by the physical properties of thesolutions and/or liquids employed. The method according to the inventionis preferably carried out at a temperature of from −100 to +250° C.,particularly preferably from −78 to +150° C. and very particularlypreferably from 0 to +40° C.

The method according to the invention can be carried out eithercontinuously or batchwise. It is preferably carried out continuously.

For carrying out the method according to the invention for the1,3-dipolar cycloaddition of organic compounds, it is necessary for thecycloaddition to be carried out as far as possible in the homogeneousliquid phase containing no or only very small solid particles, sinceotherwise the channels present in the microreactors become blocked.

The course of the 1,3-dipolar cycloaddition reaction in the methodaccording to the invention can be followed using various analyticalmethods known to the person skilled in the art and if necessaryregulated. The course of the reaction is preferably followed bychromatography, particularly preferably by high-pressure liquidchromatography, and if necessary regulated. Control of the reaction issignificantly improved in the method according to the invention comparedwith known methods.

After the reaction, the organic compounds formed are isolated ifdesired. The cycloaddition product(s) is (are) preferably isolated fromthe reaction mixture by extraction.

Organic compounds which can be employed in the method according to theinvention are all 1,3-dipolar organic compounds which are known to theperson skilled in the art and are suitable as substrate for 1,3-dipolarcycloadditions. The organic compounds are preferably selected fromaliphatic, aromatic or heteroaromatic nitrile ylides, nitrileimines,nitrile oxides, diazoalkanes, azides, azomethine ylides,azomethinimines, nitrones, carbonyl ylides, carbonylimines or carbonyloxides.

Aliphatic nitrile ylides, nitrileimines, nitrile oxides, diazoalkanes,azides, azomethine ylides, azomethinimines, nitrones, carbonyl ylides,carbonylimines or carbonyl oxides which can be employed are allaliphatic compounds from the above-mentioned classes of substance whichare known to the person skilled in the art and are suitable as substratefor 1,3-dipolar cycloadditions. Straight-chain, branched, cyclic,saturated and unsaturated compounds are also included.

Aromatic nitrile ylides, nitrileimines, nitrile oxides, diazoalkanes,azides, azomethine ylides, azomethinimines, nitrones, carbonyl ylides,carbonylimines or carbonyl oxides which can be employed are all aromaticcompounds from the above-mentioned classes of substance which are knownto the person skilled in the art and are suitable as substrate for1,3-dipolar cycloadditions. The invention thus covers compounds and/orderivatives which have a monocyclic and/or polycyclic homoaromatic basicstructure or a corresponding moiety, for example in the form ofsubstituents.

Heteroaromatic nitrile ylides, nitrileimines, nitrile oxides,diazoalkanes, azides, azomethine ylides, azomethinimines, nitrones,carbonyl ylides, carbonylimines or carbonyl oxides which can be employedare all heteroaromatic compounds from the above-mentioned classes ofsubstance which are known to the person skilled in the art and aresuitable as substrate for 1,3-dipolar cycloadditions and contain atleast one heteroatom. Heteroaromatic compounds for the purposes of theinvention include heteroaromatic compounds and/or derivatives thereofwhich contain at least one monocyclic and/or polycyclic heteroaromaticbasic structure or a corresponding moiety, for example in the form ofsubstituents. Heteroaromatic basic structures or moieties particularlypreferably include at least one oxygen, nitrogen and/or sulfur atom.

Dipolarophiles which can be employed in the method according to theinvention are all dipolarophiles which are known to the person skilledin the art and are suitable for 1,3-dipolar cycloadditions, or a mixtureof at least two dipolarophiles. Preferably, in each case only onecompound is used as dipolarophile in the method according to theinvention.

In a further preferred embodiment, the dipolarophile used is at leastone compound selected from olefins, acetylenes, aldehydes, ketones,imines, nitrites, furans, thiophenes or mixtures of thesedipolarophiles.

For the purposes of the invention, all dipolarophilic functional groupsknown to the person skilled in the art which react directly in1,3-dipolar cycloadditions may be present in the various 1,3-dipolarorganic compounds mentioned above. These compounds react inintramolecular cycloadditions if this is sterically possible. It ispossible here for only one 1,3-dipolar functional group or a combinationof at least two 1,3-dipolar functional groups and only onedipolarophilic group or a combination of at least two dipolarophilicgroups, which are in each case identical or different, to be present inthe organic compound in question. Preferably, only one 1,3-dipolarfunctional group and only one dipolarophilic functional group arepresent.

The molar ratio between the organic compound and the dipolarophileemployed in the method according to the invention is dependent on thereactivity of the organic compounds and dipolarophiles employed. Themolar ratio between the organic compound and the dipolarophile ispreferably equimolar. In a further preferred embodiment, thedipolarophile is used in a 1.3-fold to 2-fold molar excess, particularlypreferably in a 1.4-fold to 1.9-fold excess, very particularlypreferably in a 1.5-fold to 1.8-fold excess, based on the organiccompound.

The selectivity of the reaction itself depends on a number of furtherparameters in addition to the concentration of the reagents employed,such as, for example, the temperature, the type of dipolarophile used orthe residence time. It is possible for the person skilled in the art tomatch the various parameters to the particular 1,3-dipolar cycloadditionin such a way that the desired cycloaddition product(s) is (are)obtained.

It is essential for the method according to the invention that theorganic compounds and dipolarophiles employed are either themselvesliquid or are in dissolved form. If these compounds are not alreadythemselves in liquid form, they therefore have to be dissolved in asuitable solvent before the method according to the invention is carriedout. The solvents employed are preferably water, ethers, particularlypreferably diethyl ether, methyl tert-butyl ether, tetrahydrofuran ordioxane, aromatic solvents, particularly preferably toluene, xylenes,ligroin or phenyl ether, halogenated solvents, particularly preferablydichloromethane, chloroform, 1,2-dichloroethane or1,1,2,2-tetrachloroethane, or mixtures thereof.

In the method according to the invention, the risk to humans and theenvironment caused by escaping chemicals is considerably reduced andthus results in increased safety on handling of hazardous substances.The 1,3-dipolar cycloaddition of organic compounds by the methodaccording to the invention furthermore enables better control of thereaction conditions, such as, for example, reaction duration andreaction temperature, than is possible in the conventional methods.Furthermore, the risk of explosions in highly exothermic cycloadditionsis significantly reduced on use of the method according to theinvention. The temperature can be selected and kept constantindividually in each volume unit of the system. The course of the1,3-dipolar cycloaddition reaction can be regulated very quickly andprecisely in the method according to the invention. The cycloadditionproducts can thus be obtained in very good and reproducible yields.

It is also particularly advantageous that the method according to theinvention can be carried out continuously. It is thus faster and lessexpensive compared with conventional methods, and it is possible toprepare any desired amounts of the cycloaddition products without majormeasurement and regulation complexity.

The invention is explained below with reference to an example. Thisexample serves merely to explain the invention and does not restrict thegeneral inventive idea.

EXAMPLE Oxidation of 5-bromo-2-allyloxybenzaldoxime to5-bromo-2-allyloxybenzonitrile Oxide and 1,3-dipolar cycloaddition to8-bromo-3α,4-dihydro-3H-[1]-benzopyrano[4,3-c]-2-isoxazole

The oxidation of 5-bromo-2-allyloxybenzaldoxime using sodiumhypochlorite solution to give 5-bromo-2-allyloxybenzonitrile oxide andthe subsequent 1,3-dipolar cycloaddition were carried out in a staticmicromixer (Technical University of Ilmenau, Faculty of MachineConstruction, Dr. Norbert Schwesinger, Postfach 100565, D-98684 Ilmenau)having a physical size of 40 mm×25 mm×1 mm with a total of 11 mixingstages each with a volume of 0.125 μl. The total pressure loss was about1000 Pa.

The static micromixer was connected via an outlet and an Omnifitmedium-pressure HPLC connector (Omnifit, Great Britain) to a Tefloncapillary having an internal diameter of 0.49 mm and a length of 0.5 m.The reaction was carried out at room temperature, 10° C. or 0° C. In thecase of the two latter temperatures, the temperature of the staticmicromixer and the Teflon capillary was regulated in an ethanol-filleddouble-wall vessel thermostatted to 10° C. or 0° C.

A 2 ml disposable syringe was filled with part of a solution of 0.5 g (2mmol) of 5-bromo-2-allyloxybenzaldoxime and 10 ml of dichloromethane,and a further 2 ml syringe was filled with an approximately 10% aqueoussodium hypochlorite solution. The contents of the two syringes weresubsequently transferred into the static micromixer using a meteringpump (Harvard Apparatus Inc., Pump 22, South Natick, Mass., USA). Beforethe reaction was carried out, the experimental arrangement wascalibrated with respect to the dependence of the residence time on thepump flow rate. The pump rate was set in such a way that residence timesof 5, 2.5 and 1.25 minutes were achieved. The reaction was monitoredwith the aid of a Merck Hitachi LaChrom HPLC instrument. The ratios ofstarting material to product were also determined by HPLC on the aboveinstrument.

1. A method for the 1,3-dipolar cycloaddition of an organic compound,comprising mixing at least one organic compound in liquid or dissolvedform with at least one dipolarophile in liquid or dissolved form in atleast one static micromixer connected via an outlet to a capillary, andreacting for a residence time wherein the reaction mixture flows throughthe microreactor at a flow rate of 0.01 –100 ml/min, and optionallyisolating the formed organic cycloaddition product from the reactionmixture.
 2. A method according to claim 1, wherein the volume of themicroreactor is ≦100 μl.
 3. A method according to claim 1, wherein themicroreactor is heatable.
 4. A method according to claim 1, wherein themicroreactor has channels having a diameter of 10–1000 μm.
 5. A methodaccording to claim 1, wherein the reaction mixture flows through themicroreactor at a flow rate of 1 μl/min–1 ml/min.
 6. A method accordingto claim 1, wherein the residence time of the compounds employed in themicroreactor, or in the microreactor and the capillaries, is ≦15 hours.7. A method according to claim 1, wherein the method is carried out at−100–+250° C.
 8. A method according to claim 1, wherein the reaction isfollowed by chromatography.
 9. A method according to claim 1, whereinthe organic compound is an aliphatic, an aromatic or a heteroaromaticnitrile ylide, a nitrileimine, a nitrile oxide, a diazoalkane, an azide,an azomethine ylide, an azomethinimine, a nitrone, a carbonyl ylide, acarbonylimine or a carbonyl oxide.
 10. A method according to claim 1,wherein the dipolarophile is at least one compound of an olefin, anacetylene, an aldehyde, a ketone, an imine, a nitrile, a furan, athiophene or a mixture thereof.
 11. A method according to claim 1,wherein the molar ratio between the organic compound and thedipolarophile is equimolar, based on the organic compound.
 12. A methodaccording to claim 1, wherein the capillary is heatable.
 13. A methodaccording to claim 1, wherein the volume of the microreactor is ≦50 μl.14. A method according to claim 1, wherein the microreactor has channelshaving a diameter of 20 –8000 μm.
 15. A method according to claim 1,wherein the residence time of the compounds employed in themicroreactor, or in the microreactor and the capillaries, is ≦3 hour.16. A method according to claim 1, wherein the method is carried out at−78 °–150° C.
 17. A method according to claim 1, wherein the method iscarried out at 0–40° C.
 18. A method according to claim 1, wherein thereaction is followed by high-pressure liquid chromatography.
 19. Amethod according to claim 1, wherein the dipolarphile is used in a1.3-fold–2-fold molar excess, based on the organic compound.
 20. Amethod according to claim 1, wherein the dipolarphile is used in a1.4-fold–1.9-fold molar excess, based on the organic compound.
 21. Amethod according to claim 1, wherein the cycloaddition reaction isconducted in a homogeneous liquid phase.
 22. A method according to claim21, wherein the homogenous liquid phase comprises no or only very smallsolid particles.